For many decades,Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions,which are thought to be related to cognitive dysfunctions such as memory and language defi...For many decades,Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions,which are thought to be related to cognitive dysfunctions such as memory and language deficits.The exact cause of Alzheimer's disease is still under debate,making it challenging to establish an effective therapy or early diagnosis.It is widely accepted that the accumulation of amyloid-beta peptide in the brain parenchyma leads to synaptic dysfunction,a critical step in Alzheimer's disease development.The traditional amyloid cascade model is initiated by accumulating extracellular amyloid-beta in brain areas essential for memory and language.However,while it is possible to reduce the presence of amyloid-beta plaques in the brain with newer immunotherapies,cognitive symptoms do not necessarily improve.Interestingly,recent studies support the notion that early alterations in subcortical brain regions also contribute to brain damage and precognitive decline in Alzheimer's disease.A body of recent evidence suggests that early Alzheimer's disease is associated with alterations(e.g.,motivation,anxiety,and motor impairment)in subcortical areas,such as the striatum and amygdala,in both human and animal models.Also,recent data indicate that intracellular amyloid-beta appears early in subcortical regions such as the nucleus accumbens,locus coeruleus,and raphe nucleus,even without extracellular amyloid plaques.The reported effects are mainly excitatory,increasing glutamatergic transmission and neuronal excitability.In agreement,data in Alzheimer's disease patients and animal models show an increase in neuronal synchronization that leads to electroencephalogram disturbances and epilepsy.The data indicate that early subcortical brain dysfunctions might be associated with non-cognitive symptoms such as anxiety,irritability,and motivation deficits,which precede memory loss and language alterations.Overall,the evidence reviewed suggests that subcortical brain regions could explain early dysfunctions and perhaps be targets for therapies to slow disease progression.Future research should focus on these non-traditional brain regions to reveal early pathological alterations and underlying mechanisms to advance our understanding of Alzheimer's disease beyond the traditionally studied hippocampal and cortical circuits.展开更多
The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an impo...The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.展开更多
The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain functio...The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.展开更多
Neuronal activity,synaptic transmission,and molecular changes in the basolateral amygdala play critical roles in fear memory.Cylindromatosis(CYLD)is a deubiquitinase that negatively regulates the nuclear factor kappa-...Neuronal activity,synaptic transmission,and molecular changes in the basolateral amygdala play critical roles in fear memory.Cylindromatosis(CYLD)is a deubiquitinase that negatively regulates the nuclear factor kappa-B pathway.CYLD is well studied in non-neuronal cells,yet underinvestigated in the brain,where it is highly expressed.Emerging studies have shown involvement of CYLD in the remodeling of glutamatergic synapses,neuroinflammation,fear memory,and anxiety-and autism-like behaviors.However,the precise role of CYLD in glutamatergic neurons is largely unknown.Here,we first proposed involvement of CYLD in cued fear expression.We next constructed transgenic model mice with specific deletion of Cyld from glutamatergic neurons.Our results show that glutamatergic CYLD deficiency exaggerated the expression of cued fear in only male mice.Further,loss of CYLD in glutamatergic neurons resulted in enhanced neuronal activation,impaired excitatory synaptic transmission,and altered levels of glutamate receptors accompanied by over-activation of microglia in the basolateral amygdala of male mice.Altogether,our study suggests a critical role of glutamatergic CYLD in maintaining normal neuronal,synaptic,and microglial activation.This may contribute,at least in part,to cued fear expression.展开更多
In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epice...In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epicenter,and caudal penumbra of the injury site initiates a cellularmolecular interplay that acts as a rewiring mechanism leading to central neuropathic pain.Sprouting can lead to the formation of new connections triggering abnormal sensory transmission.The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity.Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen.In this study,we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury.We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters,leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting.Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control(placebo).We used von Frey monofilaments and the“up-down method”to evaluate mechanical allodynia.Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sexdependent effect.The expression profile of glutamatergic transporters(excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1)revealed a sexual dimorphism in the rostral,epicenter,and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes.Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents.Analyses of peptidergic(calcitonin gene-related peptide-α)and non-peptidergic(isolectin B4)fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/isolectin B4 ratio in comparison with sham,suggesting increased receptive fields in the dorsal horn.Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats,this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury.Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord.The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain,an area with a critical need for treatment.展开更多
In this paper,the effect of sodium laurate(SL)on the properties of sodium lauroyl glutamate(SLG),such as surface activity,foam,wetting,emulsification,and resistance to hard water,has been systematically investigated.T...In this paper,the effect of sodium laurate(SL)on the properties of sodium lauroyl glutamate(SLG),such as surface activity,foam,wetting,emulsification,and resistance to hard water,has been systematically investigated.The results showed that the critical micelle concentration(cmc)of SLG was 0.30 mmol/L,and the surface tension at the cmc(γcmc)was 34.95 mN/m.With the increase of SL content,the efficiency of SLG solution in reducing the surface tension was decreased.When the SL content was increased,there was no significant change in the foaming ability and foam stability of SLG solutions.The increase of SL content improved both the emulsification and wettability of SLG,but reduced its water resistance.展开更多
N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first ima...N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first images of native NMDARs directly extracted from rat brains,revealing key aspects of NMDAR assembly and diversity.展开更多
Ca^(2+)signaling plays crucial roles in plant stress responses,including defense against insects.To counteract insect feeding,different parts of a plant deploy systemic signaling to communicate and coordinate defense ...Ca^(2+)signaling plays crucial roles in plant stress responses,including defense against insects.To counteract insect feeding,different parts of a plant deploy systemic signaling to communicate and coordinate defense responses,but little is known about the underlying mechanisms.In this study,micrografting,in vivo imaging of Ca^(2+)and reactive oxygen species(ROS),quantification of jasmonic acid(JA)and defensive metabolites,and bioassay were used to study how Arabidopsis seedlings regulate systemic responses in leaves after hypocotyls are wounded.We show that wounding hypocotyls rapidly activated both Ca^(2+)and ROS signals in leaves.RBOHD,which functions to produce ROS,along with two glutamate receptors GLR3.3 and GLR3.6,but not individually RBOHD or GLR3.3 and GLR3.6,in hypocotyls regulate the dynamics of systemic Ca^(2+)signals in leaves.In line with the systemic Ca^(2+)signals,after wounding hypocotyl,RBOHD,GLR3.3,and GLR3.6 in hypocotyl also cooperatively regulate the transcriptome,hormone jasmonic acid,and defensive secondary metabolites in leaves of Arabidopsis seedlings,thus controlling the systemic resistance to insects.Unlike leaf-to-leaf systemic signaling,this study reveals the unique regulation of wounding-induced hypocotyl-to-leaf systemic signaling and sheds new light on how different plant organs use complex signaling pathways to modulate defense responses.展开更多
In this study,we systematically tested the hypothesis that during the critical developmental period of adolescence,on a macro scale,the concentrations of major excitatory and inhibitory neurotransmitters(glutamate/glu...In this study,we systematically tested the hypothesis that during the critical developmental period of adolescence,on a macro scale,the concentrations of major excitatory and inhibitory neurotransmitters(glutamate/glutamine andγ‑aminobutyric acid[GABA])in the dorsal and ventral lateral prefrontal cortex are associated with the brain’s functional connectivity and an individual’s psychopathology.Neurotransmitters were measured via magnetic resonance spectroscopy while functional connectivity was measured with resting-state fMRI(n=121).Seed-based and network-based analyses revealed associations of neurotransmitter concentrations and functional connectivities between regions/networks that are connected to prefrontal cortices via structural connections that are thought to be under dynamic development during adolescence.These regions tend to be boundary areas between functional networks.Furthermore,several connectivities were found to be associated with individual’s levels of internalizing psychopathology.These findings provide insights into specific neurochemical mechanisms underlying the brain’s macroscale functional organization,its development during adolescence,and its potential associations with symptoms associated with internalizing psychopathology.展开更多
BACKGROUND Diabetic peripheral neuropathy(DPN)is the most prevalent complication of type 2 diabetes mellitus(T2DM).Due to a lack of specific biomarkers,the early diagnosis of this disorder is limited.AIM To identify a...BACKGROUND Diabetic peripheral neuropathy(DPN)is the most prevalent complication of type 2 diabetes mellitus(T2DM).Due to a lack of specific biomarkers,the early diagnosis of this disorder is limited.AIM To identify and validate serum amino acids that could discriminate T2DM patients with DPN from those without DPN.METHODS T2DM patients with DPN,T2DM patients without DPN,and healthy controls were recruited for this study.The participants comprised two nonoverlapping cohorts:A training cohort(DPN=84 participants,T2DM=82 participants,normal=50 participants)and a validation cohort(DPN=112 participants,T2DM=93 participants,normal=58 participants).A prediction model of the ability of serum amino acids to distinguish DPN from T2DM was established using a logistic regression model,and area under the curve(AUC)analysis was used to evaluate the diagnostic ability of the model.In addition,the serum amino acid levels of 13 DPN patients were also detected before treatment and after 3 months of treatment.RESULTS A clinical detection method for the diagnosis of DPN based on a biomarker panel of three serum amino acids and diabetes duration was developed.The diagnostic model demonstrated AUC values of 0.805(95%CI:0.739-0.871)and 0.810(95%CI:0.750-0.870)in the training and verification cohorts,respectively.In the identification of T2DM patients and normal controls,the AUC values were 0.891(95%CI:0.836-0.945)and 0.883(95%CI:0.832-0.934)in the training and validation cohorts,respectively.Arginine and tyrosine levels were increased after treatment,whereas aspartic acid levels were decreased after treatment.CONCLUSION This study successfully identified and validated the metabolomic significance of arginine,tyrosine,and glutamic acid as potential biomarkers for diagnosing DPN.These findings are particularly valuable,as they establish a foundational step toward developing the first routine laboratory test for DPN.Moreover,the diagnostic model that was constructed in this study effectively distinguishes DPN patients from those with T2DM without neuropathy,thereby potentially facilitating early diagnosis and intervention.展开更多
BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(...BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(mGluR5)may alleviate hepatic steatosis.However,the precise mechanism warrants further exploration.AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.METHODS Free fatty acids(FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG.Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content.Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II,as well as the expression of the key signaling molecules AMPK and ULK1,in the treated cells.To further elucidate the contributions of autophagy and AMPK,we used chloroquine(CQ)to inhibit autophagy and compound C(CC)to inhibit AMPK activity.In parallel,wild-type mice and mGluR5 knockout(KO)mice fed a normal chow diet or a high-fat diet(HFD)were used to evaluate the effect of mGluR5 inhibition in vivo.RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression.The autophagy inhibitor CQ reversed the effects of MPEP.In addition,MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs.MPEP treatment led to the nuclear translocation of transcription factor EB,which is known to promote p62 expression.This effect was negated by the AMPK inhibitor CC.mGluR5 KO mice presented reduced body weight,improved glucose tolerance and reduced hyperlipidemia when fed a HFD.Additionally,the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway.These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.展开更多
Epilepsy is a chronic neurological disorder affecting~65 million individuals worldwide.Abnormal synaptic plasticity is one of the most important pathological features of this condition.We investigated how ubiquitin-sp...Epilepsy is a chronic neurological disorder affecting~65 million individuals worldwide.Abnormal synaptic plasticity is one of the most important pathological features of this condition.We investigated how ubiquitin-specific peptidase 47(USP47)influences synaptic plasticity and its link to epilepsy.We found that USP47 enhanced excitatory postsynaptic transmission and increased the density of total dendritic spines and the proportion of mature dendritic spines.Furthermore,USP47 inhibited the degradation of the ubiquitinatedα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR)subunit glutamate receptor 1(GluR1),which is associated with synaptic plasticity.In addition,elevated levels of USP47 were found in epileptic mice,and USP47 knockdown reduced the frequency and duration of seizure-like events and alleviated epileptic seizures.To summarize,we present a new mechanism whereby USP47 regulates excitatory postsynaptic plasticity through the inhibition of ubiquitinated GluR1 degradation.Modulating USP47 may offer a potential approach for controlling seizures and modifying disease progression in future therapeutic strategies.展开更多
Glutamate is an essential excitatory neurotransmitter in the brain,playing a vital role in regulating synaptic activity and maintaining the homeostasis of the cerebral environment but also serves as a central hub for ...Glutamate is an essential excitatory neurotransmitter in the brain,playing a vital role in regulating synaptic activity and maintaining the homeostasis of the cerebral environment but also serves as a central hub for neuronal injury and inflammatory responses.In various pathological conditions,such as ischemic stroke,glutamate is released and accumulates excessively in the brain,leading to heightened stimulation of neurons and excitotoxicity.This phenomenon positions glutamate as a primary inducing factor for neuronal damage following cerebral ischemia.Glutamate exerts its effects primarily through two types of receptors:ionotropic andmetabotropic glutamate receptors,both of which are extensively distributed throughout the hippocampus and cortical regions of the brain.Ionotropic receptors mediate rapid excitatory neurotransmission upon activation by glutamate;these are mainly categorized into N-methyl-D-aspartate receptors(NMDARs),α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors(AMPARs),and kainate receptors(KARs).Conversely,metabotropic receptors function asG-protein-coupled receptors(GPCR)facilitating glutamatergic cellular effects via intracellular secondmessenger.With the comprehensive investigation of glutamate receptors and their structural characteristics,our understanding of the nerve damage and protective mechanisms associated with glutamate receptors in ischemic stroke is progressively advancing.Consequently,exploring the role of glutamate receptors and their downstream signaling pathways in cerebral ischemia can provide a robust theoretical foundation for targeted therapies aimed at treating cerebral ischemia,stroke,and related disorders.This article reviews the function of glutamate receptors and theirmediated downstreamsignal transduction pathways in the context of ischemic brain injury.展开更多
AMPA Receptor and PET Tracer Limitation.The alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor(AMPAR)is a subtype of ionotropic glutamate receptor.It functions as a ligand-gated ion channel and is primar...AMPA Receptor and PET Tracer Limitation.The alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor(AMPAR)is a subtype of ionotropic glutamate receptor.It functions as a ligand-gated ion channel and is primarily responsible for rapidly transmitting the signal from glutamate in the central nervous system[1].This receptor plays a crucial role in various cognitive functions including learning,memory,cognition,synaptic plasticity,and neurodevelopment.AMPARs are typically composed of four subunits,namely GluA1,GluA2,GluA3,and GluA4,which can form homo-or hetero-tetramers.These subunits bind directly or indirectly to various scaffolding proteins such as transmembrane AMPA receptor regulatory proteins(TARPs).展开更多
Recent studies show that a reduced effect of inhibitory transmitter system in the visual cortex may underlie aged visual function degradation. Whether excitatory transmitter system changes with age and hence affects i...Recent studies show that a reduced effect of inhibitory transmitter system in the visual cortex may underlie aged visual function degradation. Whether excitatory transmitter system changes with age and hence affects intracortical excitation-inhibition balance is not clear. To explore this issue, we used Nissl staining and immunohistochemical methods as well as Image-Pro Express software to examine the density of Nissl-stained neurons, Glutamie acid-immunoreactive （Glu-IR） neurons and T-Aminobutyric acid-immunoreactive （GABA-IR） neurons in the primary visual cortex of young adult and aged cats. The results showed that there was no significant difference in the density of Nissl-stained neurons between young and old cats （2〉0.05）. However, the density of Glu-IR neurons and GABA-IR neurons in the primary visual cortex of aged cats was significantly lower than that of young ones （P〈0.01）. The ratio between Glu-IR neurons and GABA-IR neurons was significantly increased in old cats compared to that in young adult ones （P〈0.01）. These results indicated that the effect of excitatory transmitter system in the old visual cortex was increased relative to the inhibitory transmitter system, which might cause an imbalance between cortical excitation and inhibition and might be an important factor mediating the visual function decline during aging.展开更多
Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and y-aminobutyric acid （GABA） in the hippocampal ventral sub...Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and y-aminobutyric acid （GABA） in the hippocampal ventral subiculum, which play a critical role in the reinstatement of drug-seeking behavior induced by environmental cues. Methods Conditioning place preference （CPP） and conditioning place aversion （CPA） models were used to establish environment associated with rewarding and aversive properties of morphine respectively. Microdialysis and high performance liquid chromatography were used to measure the extracelluar level of glutamate and GABA in the ventral subiculum under these environmental cues. Results Exposure to the environmental cues associated with rewarding properties of morphine resulted in a decrease （approximately 11%） of extracellular level of GABA in ventral subiculum, and exposure to the environmental cues associated with aversive properties of morphine resulted in an increase （approximately 230%） of extracellular level of glutamate in ventral subiculum. Conclusion Environmental cues associated with different properties of morphine modulate the release of distinct neurotransmitters in the hippocampal ventral subiculum possibly through different neural circuit.展开更多
Layered double Mg-Fe-CO3 hydroxide （Mg-Fe-LDH） with a mole ratio of Mg to Fe of 3 was synthesized by coprecipitation method and calcined product Mg-Fe-CLDH was obtained by heating Mg-Fe-LDH at 500 ℃ for 6 h. The as...Layered double Mg-Fe-CO3 hydroxide （Mg-Fe-LDH） with a mole ratio of Mg to Fe of 3 was synthesized by coprecipitation method and calcined product Mg-Fe-CLDH was obtained by heating Mg-Fe-LDH at 500 ℃ for 6 h. The as prepared Mg-Fe-LDH and calcined Mg-Fe-CLDH were used for removal of glutamic acid （Glu） from aqueous solution, respectively. Batch studies were carried out to address various experimental parameters such as contact time, pH, initial glutamic acid （Glu） concentration, co-existing anions and temperature. Glu was removed effectively （99.9%） under the optimized experimental conditions with Mg-Fe-CLDH. The adsorption kinetics follows the Ho’s pseudo second-order model. Isotherms for adsorption with Mg-Fe-CLDH at different solution temperatures were well described using the Langmuir model with a good correlation coefficient. The intraparticle diffusion model fitted the data well, which suggests that the intraparticle diffusion is not only the rate-limiting step.展开更多
The line of T240-6 was selected from 32 SC 2 lines of immature embryo culture of T240 (common wheat (Triticum aestivum L.)× Wheat-Haynaldia villosa (L.) Schur. 6D/6V substitution line) through powdery mildew ch...The line of T240-6 was selected from 32 SC 2 lines of immature embryo culture of T240 (common wheat (Triticum aestivum L.)× Wheat-Haynaldia villosa (L.) Schur. 6D/6V substitution line) through powdery mildew characterization, glutamate oxaloacetate transaminase (GOT) enzyme and gliadin (Gli) analyses and in situ hybridization. All of the individual plants resistant to powdery mildew lacked the locus of GOT at 6VL arm (GOT-V 2) and had gliadin locus at 6VS arm (Gli-V 2) of Haynaldia villosa. All the plants resistant to powdery mildew had one or two telocentric chromosomes that did not pair with wheat chromosomes but paired between themselves. T240-6 was identified as a telocentric line through in situ hybridization.展开更多
OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depre...OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depression,but more and more evidence indicates that glutamatergic transmission may be the key factor leading to the occurrence of depression. However,the role of the membrane expression and regulation of glutamate receptors in the development of depression has not been elucidated. To address this issue,we have done series of experiments. METHODS Different methods and techniques,such as behavior,morphology,molecular biology and electrophysiology,were applied to investigate the impact of glutamate receptors and their subunits in the regulation of synaptic plasticity and the mechanism in depressive animal models. RESULTS Chronic social defeat stress(CSDS) can induce depressive behaviors in wildtype(WT) mice but not caspase-1 knockout(KO) mice. Further experiments showed that,in WT mice,CSDS induced a significant decrease in the membrane expression levels of the GluR1 and GluR2 subunits of AMPA receptors,the amplitudes of m EPSC in hippocampal CA1,meanwhile the long-term potentiation(LTP) at hippocampus SC-CA1 pathway was also impaired. Oppositely,this CSDS-induced reduction of the membrane expression of AMPA receptors was prevented by the knockout of caspase-1 or caspase-1 inhibitor,in which the expression of GluA1 and GluA2 were upregulated from(60.2±3.4)% and(63.9±3.7)% to(120.1±5.9)%and(112.6±9.6)%,respectively,while the total protein level of AMPA receptor subunits were not affected.On the other hand,a chronic intracerebroventricular injection of IL-1β,a downstream signal molecule of caspase-1,could induce depression-and anxiety-like behaviors in caspase-1 KO mice. CONCLUSION The caspase-1 can mediate the stress-induced depression-like behaviors by down-regulation of the membrane expression of AMPA receptors in hippocampus,the inhibition or knock-out of caspase-1can increase the expression of AMPA receptors in the membrane,thus reversing the depression-like behavior. Caspase-1 may serve as new target for depression therapy.展开更多
A full_length cDNA has been cloned encoding nicotinamide adenine dinucleotide phosphate_specific glutamate dehydrogenase (NADP_GDH) from Chlorella sorokiniana with the RT_PCR method. The complete nucleotide sequence o...A full_length cDNA has been cloned encoding nicotinamide adenine dinucleotide phosphate_specific glutamate dehydrogenase (NADP_GDH) from Chlorella sorokiniana with the RT_PCR method. The complete nucleotide sequence of NADP_GDH gene had 94% homology to the previously reported one . The NADP_GDH gene was constructed into a vector highly expressed in plants. The specific activity of NADP_GDH in transformants was detected, but not in the control plants. All transformed shoots on MS medium containing lower concentration of nitrogen and the transformed seedlings grown in lower concentration of nitrogen vermiculite had higher growth rate and more leaves than the control plants. Transformed leaf discs cultured on MS medium containing different nitrogen concentrations had more chlorophyll contents compared to the controls. These results suggested that exogenous NADP_GDH may enhance the absorption and utilization to ammonium in plants. The increased weight of transformed leaf discs cultured on medium supplemented with different concentrations of phosphinothricin (PPT) was more than that of control discs. 0.5 μg/mL PPT could be used as a selecting drug instead of kanamycin to develop the transformants. These results suggested that the NADP_GDH gene might be used as a new selecting gene in the future research of plant gene engineering.展开更多
文摘For many decades,Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions,which are thought to be related to cognitive dysfunctions such as memory and language deficits.The exact cause of Alzheimer's disease is still under debate,making it challenging to establish an effective therapy or early diagnosis.It is widely accepted that the accumulation of amyloid-beta peptide in the brain parenchyma leads to synaptic dysfunction,a critical step in Alzheimer's disease development.The traditional amyloid cascade model is initiated by accumulating extracellular amyloid-beta in brain areas essential for memory and language.However,while it is possible to reduce the presence of amyloid-beta plaques in the brain with newer immunotherapies,cognitive symptoms do not necessarily improve.Interestingly,recent studies support the notion that early alterations in subcortical brain regions also contribute to brain damage and precognitive decline in Alzheimer's disease.A body of recent evidence suggests that early Alzheimer's disease is associated with alterations(e.g.,motivation,anxiety,and motor impairment)in subcortical areas,such as the striatum and amygdala,in both human and animal models.Also,recent data indicate that intracellular amyloid-beta appears early in subcortical regions such as the nucleus accumbens,locus coeruleus,and raphe nucleus,even without extracellular amyloid plaques.The reported effects are mainly excitatory,increasing glutamatergic transmission and neuronal excitability.In agreement,data in Alzheimer's disease patients and animal models show an increase in neuronal synchronization that leads to electroencephalogram disturbances and epilepsy.The data indicate that early subcortical brain dysfunctions might be associated with non-cognitive symptoms such as anxiety,irritability,and motivation deficits,which precede memory loss and language alterations.Overall,the evidence reviewed suggests that subcortical brain regions could explain early dysfunctions and perhaps be targets for therapies to slow disease progression.Future research should focus on these non-traditional brain regions to reveal early pathological alterations and underlying mechanisms to advance our understanding of Alzheimer's disease beyond the traditionally studied hippocampal and cortical circuits.
基金supported by the National Natural Science Foundation of China,No.82371444(to YZ)the Natural Science Foundation of Hubei Province,No.2022CFB216(to XC)the Key Research Project of Ministry of Science and Technology of China,No.2022ZD021160(to YZ)。
文摘The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.
基金supported by the National Natural Science Foundation of China,Nos.32371070 (to JT),31761163005 (to JT),32100824 (to QX)the Shenzhen Science and Technology Program,Nos.RCBS20210609104606024 (to QX),JCY20210324101813035 (to DL)+4 种基金the Guangdong Provincial Key S&T Program,No.2018B030336001 (to JT)the Key Basic Research Program of Shenzhen Science and Technology Innovation Commission,Nos.JCYJ20200109115405930 (to JT),JCYJ20220818101615033 (to DL),JCYJ20210324115811031 (to QX),JCYJ20200109150717745 (to QX)Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases,No.ZDSYS20220304163558001 (to JT)Guangdong Provincial Key Laboratory of Brain Connectome and Behavior,No.2023B1212060055 (to JT)the China Postdoctoral Science Foundation,No.2021M693298 (to QX)。
文摘The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.
基金supported by the National Natural Science Foundation of China,Nos.32371065(to CL)and 32170950(to LY)the Natural Science Foundation of the Guangdong Province,No.2023A1515010899(to CL)the Science and Technology Projects in Guangzhou,Nos.2023A4J0578 and 2024A03J0180(to CW)。
文摘Neuronal activity,synaptic transmission,and molecular changes in the basolateral amygdala play critical roles in fear memory.Cylindromatosis(CYLD)is a deubiquitinase that negatively regulates the nuclear factor kappa-B pathway.CYLD is well studied in non-neuronal cells,yet underinvestigated in the brain,where it is highly expressed.Emerging studies have shown involvement of CYLD in the remodeling of glutamatergic synapses,neuroinflammation,fear memory,and anxiety-and autism-like behaviors.However,the precise role of CYLD in glutamatergic neurons is largely unknown.Here,we first proposed involvement of CYLD in cued fear expression.We next constructed transgenic model mice with specific deletion of Cyld from glutamatergic neurons.Our results show that glutamatergic CYLD deficiency exaggerated the expression of cued fear in only male mice.Further,loss of CYLD in glutamatergic neurons resulted in enhanced neuronal activation,impaired excitatory synaptic transmission,and altered levels of glutamate receptors accompanied by over-activation of microglia in the basolateral amygdala of male mice.Altogether,our study suggests a critical role of glutamatergic CYLD in maintaining normal neuronal,synaptic,and microglial activation.This may contribute,at least in part,to cued fear expression.
基金supported by COBRE(P30GM149367)the Puerto Rico Science&Technology Trust(2022-00125)+1 种基金MBRS-RISE Program(R25 GM061838)SC1GM144032 program(all to JDM)。
文摘In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epicenter,and caudal penumbra of the injury site initiates a cellularmolecular interplay that acts as a rewiring mechanism leading to central neuropathic pain.Sprouting can lead to the formation of new connections triggering abnormal sensory transmission.The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity.Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen.In this study,we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury.We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters,leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting.Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control(placebo).We used von Frey monofilaments and the“up-down method”to evaluate mechanical allodynia.Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sexdependent effect.The expression profile of glutamatergic transporters(excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1)revealed a sexual dimorphism in the rostral,epicenter,and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes.Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents.Analyses of peptidergic(calcitonin gene-related peptide-α)and non-peptidergic(isolectin B4)fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/isolectin B4 ratio in comparison with sham,suggesting increased receptive fields in the dorsal horn.Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats,this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury.Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord.The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain,an area with a critical need for treatment.
文摘In this paper,the effect of sodium laurate(SL)on the properties of sodium lauroyl glutamate(SLG),such as surface activity,foam,wetting,emulsification,and resistance to hard water,has been systematically investigated.The results showed that the critical micelle concentration(cmc)of SLG was 0.30 mmol/L,and the surface tension at the cmc(γcmc)was 34.95 mN/m.With the increase of SL content,the efficiency of SLG solution in reducing the surface tension was decreased.When the SL content was increased,there was no significant change in the foaming ability and foam stability of SLG solutions.The increase of SL content improved both the emulsification and wettability of SLG,but reduced its water resistance.
文摘N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first images of native NMDARs directly extracted from rat brains,revealing key aspects of NMDAR assembly and diversity.
基金National Natural Science Foundation of China(U23A20199)Yunnan Revitalization Talent Support Program“Yunling Scholar”and Yunnan Fundamental Research Projects(202201AS070056)。
文摘Ca^(2+)signaling plays crucial roles in plant stress responses,including defense against insects.To counteract insect feeding,different parts of a plant deploy systemic signaling to communicate and coordinate defense responses,but little is known about the underlying mechanisms.In this study,micrografting,in vivo imaging of Ca^(2+)and reactive oxygen species(ROS),quantification of jasmonic acid(JA)and defensive metabolites,and bioassay were used to study how Arabidopsis seedlings regulate systemic responses in leaves after hypocotyls are wounded.We show that wounding hypocotyls rapidly activated both Ca^(2+)and ROS signals in leaves.RBOHD,which functions to produce ROS,along with two glutamate receptors GLR3.3 and GLR3.6,but not individually RBOHD or GLR3.3 and GLR3.6,in hypocotyls regulate the dynamics of systemic Ca^(2+)signals in leaves.In line with the systemic Ca^(2+)signals,after wounding hypocotyl,RBOHD,GLR3.3,and GLR3.6 in hypocotyl also cooperatively regulate the transcriptome,hormone jasmonic acid,and defensive secondary metabolites in leaves of Arabidopsis seedlings,thus controlling the systemic resistance to insects.Unlike leaf-to-leaf systemic signaling,this study reveals the unique regulation of wounding-induced hypocotyl-to-leaf systemic signaling and sheds new light on how different plant organs use complex signaling pathways to modulate defense responses.
基金supported by NIMH grant R01105501(PI:MTB and BLK).
文摘In this study,we systematically tested the hypothesis that during the critical developmental period of adolescence,on a macro scale,the concentrations of major excitatory and inhibitory neurotransmitters(glutamate/glutamine andγ‑aminobutyric acid[GABA])in the dorsal and ventral lateral prefrontal cortex are associated with the brain’s functional connectivity and an individual’s psychopathology.Neurotransmitters were measured via magnetic resonance spectroscopy while functional connectivity was measured with resting-state fMRI(n=121).Seed-based and network-based analyses revealed associations of neurotransmitter concentrations and functional connectivities between regions/networks that are connected to prefrontal cortices via structural connections that are thought to be under dynamic development during adolescence.These regions tend to be boundary areas between functional networks.Furthermore,several connectivities were found to be associated with individual’s levels of internalizing psychopathology.These findings provide insights into specific neurochemical mechanisms underlying the brain’s macroscale functional organization,its development during adolescence,and its potential associations with symptoms associated with internalizing psychopathology.
基金Supported by the Youth Fund for Specialized Clinical Research of the Health Commission,No.20214Y0149.
文摘BACKGROUND Diabetic peripheral neuropathy(DPN)is the most prevalent complication of type 2 diabetes mellitus(T2DM).Due to a lack of specific biomarkers,the early diagnosis of this disorder is limited.AIM To identify and validate serum amino acids that could discriminate T2DM patients with DPN from those without DPN.METHODS T2DM patients with DPN,T2DM patients without DPN,and healthy controls were recruited for this study.The participants comprised two nonoverlapping cohorts:A training cohort(DPN=84 participants,T2DM=82 participants,normal=50 participants)and a validation cohort(DPN=112 participants,T2DM=93 participants,normal=58 participants).A prediction model of the ability of serum amino acids to distinguish DPN from T2DM was established using a logistic regression model,and area under the curve(AUC)analysis was used to evaluate the diagnostic ability of the model.In addition,the serum amino acid levels of 13 DPN patients were also detected before treatment and after 3 months of treatment.RESULTS A clinical detection method for the diagnosis of DPN based on a biomarker panel of three serum amino acids and diabetes duration was developed.The diagnostic model demonstrated AUC values of 0.805(95%CI:0.739-0.871)and 0.810(95%CI:0.750-0.870)in the training and verification cohorts,respectively.In the identification of T2DM patients and normal controls,the AUC values were 0.891(95%CI:0.836-0.945)and 0.883(95%CI:0.832-0.934)in the training and validation cohorts,respectively.Arginine and tyrosine levels were increased after treatment,whereas aspartic acid levels were decreased after treatment.CONCLUSION This study successfully identified and validated the metabolomic significance of arginine,tyrosine,and glutamic acid as potential biomarkers for diagnosing DPN.These findings are particularly valuable,as they establish a foundational step toward developing the first routine laboratory test for DPN.Moreover,the diagnostic model that was constructed in this study effectively distinguishes DPN patients from those with T2DM without neuropathy,thereby potentially facilitating early diagnosis and intervention.
基金Supported by National Natural Science Foundation of China,No.81800771 and No.81300702.
文摘BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(mGluR5)may alleviate hepatic steatosis.However,the precise mechanism warrants further exploration.AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.METHODS Free fatty acids(FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG.Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content.Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II,as well as the expression of the key signaling molecules AMPK and ULK1,in the treated cells.To further elucidate the contributions of autophagy and AMPK,we used chloroquine(CQ)to inhibit autophagy and compound C(CC)to inhibit AMPK activity.In parallel,wild-type mice and mGluR5 knockout(KO)mice fed a normal chow diet or a high-fat diet(HFD)were used to evaluate the effect of mGluR5 inhibition in vivo.RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression.The autophagy inhibitor CQ reversed the effects of MPEP.In addition,MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs.MPEP treatment led to the nuclear translocation of transcription factor EB,which is known to promote p62 expression.This effect was negated by the AMPK inhibitor CC.mGluR5 KO mice presented reduced body weight,improved glucose tolerance and reduced hyperlipidemia when fed a HFD.Additionally,the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway.These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.
基金supported by grants from the National Natural Science Foundation of China(82071458 and 32160190)the United Foundation of Zunyi Municipality(Zunshikehe HZ Zi(2021)14)+3 种基金the Science and Technology Project of Guizhou Provincial Health Commission(gzwkj2021-020)the Guizhou Epilepsy Basic and Clinical Research Scientific,Technological Innovation Talent Team Project(CXTD[2022]013)the Excellent Young Talents Training Program of the Affiliated Hospital of Zunyi Medical University(rc220220906)the Guizhou Provincial Hundred Level Innovative Talents Funds(GCC-2022-038-1).
文摘Epilepsy is a chronic neurological disorder affecting~65 million individuals worldwide.Abnormal synaptic plasticity is one of the most important pathological features of this condition.We investigated how ubiquitin-specific peptidase 47(USP47)influences synaptic plasticity and its link to epilepsy.We found that USP47 enhanced excitatory postsynaptic transmission and increased the density of total dendritic spines and the proportion of mature dendritic spines.Furthermore,USP47 inhibited the degradation of the ubiquitinatedα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR)subunit glutamate receptor 1(GluR1),which is associated with synaptic plasticity.In addition,elevated levels of USP47 were found in epileptic mice,and USP47 knockdown reduced the frequency and duration of seizure-like events and alleviated epileptic seizures.To summarize,we present a new mechanism whereby USP47 regulates excitatory postsynaptic plasticity through the inhibition of ubiquitinated GluR1 degradation.Modulating USP47 may offer a potential approach for controlling seizures and modifying disease progression in future therapeutic strategies.
基金supported by Grants of the National Natural Science Foundation of China(82073831)Natural Science Foundation of Chongqing(CSTB2023NSCQ-MSX0656)China Postdoctoral Science Foundation(2023M733889).
文摘Glutamate is an essential excitatory neurotransmitter in the brain,playing a vital role in regulating synaptic activity and maintaining the homeostasis of the cerebral environment but also serves as a central hub for neuronal injury and inflammatory responses.In various pathological conditions,such as ischemic stroke,glutamate is released and accumulates excessively in the brain,leading to heightened stimulation of neurons and excitotoxicity.This phenomenon positions glutamate as a primary inducing factor for neuronal damage following cerebral ischemia.Glutamate exerts its effects primarily through two types of receptors:ionotropic andmetabotropic glutamate receptors,both of which are extensively distributed throughout the hippocampus and cortical regions of the brain.Ionotropic receptors mediate rapid excitatory neurotransmission upon activation by glutamate;these are mainly categorized into N-methyl-D-aspartate receptors(NMDARs),α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors(AMPARs),and kainate receptors(KARs).Conversely,metabotropic receptors function asG-protein-coupled receptors(GPCR)facilitating glutamatergic cellular effects via intracellular secondmessenger.With the comprehensive investigation of glutamate receptors and their structural characteristics,our understanding of the nerve damage and protective mechanisms associated with glutamate receptors in ischemic stroke is progressively advancing.Consequently,exploring the role of glutamate receptors and their downstream signaling pathways in cerebral ischemia can provide a robust theoretical foundation for targeted therapies aimed at treating cerebral ischemia,stroke,and related disorders.This article reviews the function of glutamate receptors and theirmediated downstreamsignal transduction pathways in the context of ischemic brain injury.
基金supported by the National Natural Science Foundation of China(32371066)the Guangdong Basic and Applied Basic Research Foundation(2022A1515010134)+1 种基金the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(NYKFKT2019009)the Shenzhen Technological Research Center for Primate Translational Medicine(XMHT20220104005).
文摘AMPA Receptor and PET Tracer Limitation.The alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor(AMPAR)is a subtype of ionotropic glutamate receptor.It functions as a ligand-gated ion channel and is primarily responsible for rapidly transmitting the signal from glutamate in the central nervous system[1].This receptor plays a crucial role in various cognitive functions including learning,memory,cognition,synaptic plasticity,and neurodevelopment.AMPARs are typically composed of four subunits,namely GluA1,GluA2,GluA3,and GluA4,which can form homo-or hetero-tetramers.These subunits bind directly or indirectly to various scaffolding proteins such as transmembrane AMPA receptor regulatory proteins(TARPs).
基金Natural Science Fund of Anhui Province (070413138)Key Laboratory Foundation of Anhui Province for Researches on the Conservation and Utilization of Important Biological ResourceKey Laboratory Foundation for Universities and Colleges in Anhui
文摘Recent studies show that a reduced effect of inhibitory transmitter system in the visual cortex may underlie aged visual function degradation. Whether excitatory transmitter system changes with age and hence affects intracortical excitation-inhibition balance is not clear. To explore this issue, we used Nissl staining and immunohistochemical methods as well as Image-Pro Express software to examine the density of Nissl-stained neurons, Glutamie acid-immunoreactive （Glu-IR） neurons and T-Aminobutyric acid-immunoreactive （GABA-IR） neurons in the primary visual cortex of young adult and aged cats. The results showed that there was no significant difference in the density of Nissl-stained neurons between young and old cats （2〉0.05）. However, the density of Glu-IR neurons and GABA-IR neurons in the primary visual cortex of aged cats was significantly lower than that of young ones （P〈0.01）. The ratio between Glu-IR neurons and GABA-IR neurons was significantly increased in old cats compared to that in young adult ones （P〈0.01）. These results indicated that the effect of excitatory transmitter system in the old visual cortex was increased relative to the inhibitory transmitter system, which might cause an imbalance between cortical excitation and inhibition and might be an important factor mediating the visual function decline during aging.
基金supported by the National Natural Science Foundation of China(No.30230130 and No.30400129)the Ministry of Science and Technology of China(No.2003CB515405,No.2005CB522406)+1 种基金the Program for Changjiang Scholars and Innovative Research Team of Ministry of Education of ChinaShanghai Municipal Commission for Science and Technology(No.06JC14008).
文摘Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and y-aminobutyric acid （GABA） in the hippocampal ventral subiculum, which play a critical role in the reinstatement of drug-seeking behavior induced by environmental cues. Methods Conditioning place preference （CPP） and conditioning place aversion （CPA） models were used to establish environment associated with rewarding and aversive properties of morphine respectively. Microdialysis and high performance liquid chromatography were used to measure the extracelluar level of glutamate and GABA in the ventral subiculum under these environmental cues. Results Exposure to the environmental cues associated with rewarding properties of morphine resulted in a decrease （approximately 11%） of extracellular level of GABA in ventral subiculum, and exposure to the environmental cues associated with aversive properties of morphine resulted in an increase （approximately 230%） of extracellular level of glutamate in ventral subiculum. Conclusion Environmental cues associated with different properties of morphine modulate the release of distinct neurotransmitters in the hippocampal ventral subiculum possibly through different neural circuit.
基金Project(21176263)supported by the National Natural Science Foundation of China
文摘Layered double Mg-Fe-CO3 hydroxide （Mg-Fe-LDH） with a mole ratio of Mg to Fe of 3 was synthesized by coprecipitation method and calcined product Mg-Fe-CLDH was obtained by heating Mg-Fe-LDH at 500 ℃ for 6 h. The as prepared Mg-Fe-LDH and calcined Mg-Fe-CLDH were used for removal of glutamic acid （Glu） from aqueous solution, respectively. Batch studies were carried out to address various experimental parameters such as contact time, pH, initial glutamic acid （Glu） concentration, co-existing anions and temperature. Glu was removed effectively （99.9%） under the optimized experimental conditions with Mg-Fe-CLDH. The adsorption kinetics follows the Ho’s pseudo second-order model. Isotherms for adsorption with Mg-Fe-CLDH at different solution temperatures were well described using the Langmuir model with a good correlation coefficient. The intraparticle diffusion model fitted the data well, which suggests that the intraparticle diffusion is not only the rate-limiting step.
文摘The line of T240-6 was selected from 32 SC 2 lines of immature embryo culture of T240 (common wheat (Triticum aestivum L.)× Wheat-Haynaldia villosa (L.) Schur. 6D/6V substitution line) through powdery mildew characterization, glutamate oxaloacetate transaminase (GOT) enzyme and gliadin (Gli) analyses and in situ hybridization. All of the individual plants resistant to powdery mildew lacked the locus of GOT at 6VL arm (GOT-V 2) and had gliadin locus at 6VS arm (Gli-V 2) of Haynaldia villosa. All the plants resistant to powdery mildew had one or two telocentric chromosomes that did not pair with wheat chromosomes but paired between themselves. T240-6 was identified as a telocentric line through in situ hybridization.
文摘OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depression,but more and more evidence indicates that glutamatergic transmission may be the key factor leading to the occurrence of depression. However,the role of the membrane expression and regulation of glutamate receptors in the development of depression has not been elucidated. To address this issue,we have done series of experiments. METHODS Different methods and techniques,such as behavior,morphology,molecular biology and electrophysiology,were applied to investigate the impact of glutamate receptors and their subunits in the regulation of synaptic plasticity and the mechanism in depressive animal models. RESULTS Chronic social defeat stress(CSDS) can induce depressive behaviors in wildtype(WT) mice but not caspase-1 knockout(KO) mice. Further experiments showed that,in WT mice,CSDS induced a significant decrease in the membrane expression levels of the GluR1 and GluR2 subunits of AMPA receptors,the amplitudes of m EPSC in hippocampal CA1,meanwhile the long-term potentiation(LTP) at hippocampus SC-CA1 pathway was also impaired. Oppositely,this CSDS-induced reduction of the membrane expression of AMPA receptors was prevented by the knockout of caspase-1 or caspase-1 inhibitor,in which the expression of GluA1 and GluA2 were upregulated from(60.2±3.4)% and(63.9±3.7)% to(120.1±5.9)%and(112.6±9.6)%,respectively,while the total protein level of AMPA receptor subunits were not affected.On the other hand,a chronic intracerebroventricular injection of IL-1β,a downstream signal molecule of caspase-1,could induce depression-and anxiety-like behaviors in caspase-1 KO mice. CONCLUSION The caspase-1 can mediate the stress-induced depression-like behaviors by down-regulation of the membrane expression of AMPA receptors in hippocampus,the inhibition or knock-out of caspase-1can increase the expression of AMPA receptors in the membrane,thus reversing the depression-like behavior. Caspase-1 may serve as new target for depression therapy.
文摘A full_length cDNA has been cloned encoding nicotinamide adenine dinucleotide phosphate_specific glutamate dehydrogenase (NADP_GDH) from Chlorella sorokiniana with the RT_PCR method. The complete nucleotide sequence of NADP_GDH gene had 94% homology to the previously reported one . The NADP_GDH gene was constructed into a vector highly expressed in plants. The specific activity of NADP_GDH in transformants was detected, but not in the control plants. All transformed shoots on MS medium containing lower concentration of nitrogen and the transformed seedlings grown in lower concentration of nitrogen vermiculite had higher growth rate and more leaves than the control plants. Transformed leaf discs cultured on MS medium containing different nitrogen concentrations had more chlorophyll contents compared to the controls. These results suggested that exogenous NADP_GDH may enhance the absorption and utilization to ammonium in plants. The increased weight of transformed leaf discs cultured on medium supplemented with different concentrations of phosphinothricin (PPT) was more than that of control discs. 0.5 μg/mL PPT could be used as a selecting drug instead of kanamycin to develop the transformants. These results suggested that the NADP_GDH gene might be used as a new selecting gene in the future research of plant gene engineering.
